Fibrinogen receptor antagonists

ABSTRACT

Novel fibrinogen receptor antagonists of the formula ##STR1## are provided in which the claimed compounds exhibit fibrinogen receptor antagonist activity, inhibit platelet aggregation and are therefore useful in modulating thrombus formation.

BACKGROUND OF THE INVENTION

The invention relates generally to modulating cell adhesion and toinhibiting the binding of fibrinogen and other proteins to bloodplatelets, and inhibiting the aggregation of blood plateletsspecifically to the IIb/IIIa fibrinogen receptor site. Fibrinogen is aglycoprotein present in blood plasma that participates in plateletaggregation and in fibrin formation. Platelets are cell-like anucleatedfragments, found in the blood of all mammals, that also participate inblood coagulation. Interaction of fibrinogen with the IIb/IIIa receptorsite is known to be essential for normal platelet function.

When a blood vessel is damaged by an injury or other causative factor,platelets adhere to the disrupted subendothethial surface. The adherentplatelets subsequently release biologically active constituents andaggregate. Aggregation is initiated by the binding of agonists, such asthrombin, epinephrine, or ADP to specific platelet membrane receptors.Stimulation by agonists results in exposure of latent fibrinogenreceptors on the platelet surface, and binding of fibrinogen to theglycoprotein IIb/IIIa receptor complex.

Attempts have been made to use natural products and synthetic peptidesto determine the mechanism of adhesion and platelet aggregation. Forexample, Rouslahti and Pierschbacher in Science, 238, 491-497 (1987),describe adhesive proteins such as fibronectin, vitronectin,osteopontin, collagens, thrombospondin, fibrinogen, and von Willebrandfactor that are present in extracellular matrices and in blood. Theproteins contain the tripeptide arginine-glycine-aspartic acid (RGD) astheir glycoprotein IIb/IIIa recognition site. Thesearginine-glycine-aspartic acid containing tripeptides are recognized byat least one member of a family of structurally related receptors,integrins, which are heterodimeric proteins with two membrane-spanningsubunits. The authors state that the conformation of the tripeptidesequence in the individual proteins may be critical to recognitionspecificity.

Cheresh in Proc. Nat'l Acad. Sci. U.S.A., 84, 6471-6475, (1987),describes an Arg-Gly-Asp directed adhesion receptor expressed by humanendothethial cells that is structurally similar to the IIb/IIIa complexon platelets but is antigentically and functionally distinct. Thisreceptor is directly involved in endothelial cell attachment tofibrinogen, von Willebrand factor, and vitronectin.

Pierschbacher and Rouslahti, in J. of Biol. Chem., 262, (36),17294-17298 (1987) hypothesized that the Arg-Gly-Asp sequence alonewould be a sufficient signal for receptor recognition and binding andthat, therefore, the conformation of the tri-peptide sequence would bedeterminative. Various synthetic peptides were produced and the authorsconcluded that the sterochemical conformation of Arg-Gly-Asp asinfluenced by enantiomeric substitutions or additions to this sequencesignificantly influenced receptor-ligand interaction. The authorsfurther showed that cyclization of a decapeptide by forming a disulfidebridge between non-terminal residues Pen and Cys, rendered the peptidemuch less effective at inhibiting attachment to fibronectin.

In Proc. Nat'l Acad. Sci. U.S.A., 81, 5985-5988 (1984), the same authorsdescribe tetrapeptide variants of the cell recognition site offibronectin that retain attachment-promoting activity. Peptides having atetrapeptide recognition site are described in U.S. Pat. Nos. 4,589,881and 4,614,517. A number of large polypeptide fragments in thecell-binding domain of fibronectin have cell-attachment activity. Forexample, see U.S. Pat. Nos. 4,517,686, 4,661,111 and U.S. Pat. No.4,578,079.

Ruggeri et al., Proc. Nat'l Acad. Sci. U.S.A., 83, 5708-5712 (1986)explore a series of synehetic peptides designed in lengths to 16residues, that contain RGD and a valine attached to the aspartic acidresidue of RGD that inhibit fibrinogen binding to platelets. See alsoKoczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al., J.Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blood66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App.Nos. 275,748 and 298,820.

A number of low molecular weight polypeptide factors have been isolatedfrom shake venom. These factors apparently have high affinity for thegpIIb/IIIa complex. For example, Huang et al., J. Biol Chem., 262,16157-16163 (1987); Huang et al., Biochemistry 28, 661-666 (1989)describe the primary structure of the venom trigramin which is a 72amino acid polypeptide that contains the RGD subunit. Echistatin isanother venom which has high affinity for the gpIIb/IIIa complex. Thispolypeptide contains 49 amino acids and has the RGD subunit and variousdisulfide bridges. Gan et al., J. Biol. Chem., 263, 19827-19832 (1988).See also, Dennis et al., Proc. Nat'l Acad. Sci. U.S.A., 87, 2471-2475(1989). However, these snake venom factors also have high affinity forother members of the adhesive protein receptor family including thevitronectin and fibronectin receptors so are not selective for thegpIIb/IIIa complex.

While it is known that the tripeptide sequence Arg-Gly-Asp is present incertain polypeptides that can duplicate or inhibit the cellattachment-promoting effects of fibronectin and vitronectin, thetri-peptide Arg-Gly-Asp has low activity. At present, there is littleunderstanding of how other amino acids coupled to this sequenceinfluence binding specificity. U.S. Pat. No. 5,023,233, assigned toMerck & Co., Inc., discloses small cyclic hexapeptides which contain thesequence Arg-Gly-Asp and are useful platelet aggregation inhibitors.U.S. Pat. No. 5,037,808 discloses the use of indolylplatelet-aggregation inhibitors which are believed to act byantagonizing interactions between fibrinogen and/or extracellular matrixproteins and the platelet gpIIb/IIIa receptor. U.S. Pat. No. 5,037,808discloses guanidino peptide mimetic compounds that retain an Asp residuewhich inhibit platelet aggregation. The application PCT/US90/02746describes the use of antibody-polypeptide conjugates wherein saidpolypeptides contain the Arg-Gly-Asp (RGD) sequence.

The application PCT/US91/00564 discloses the use of large cyclicpeptides containing RGD flanked by proline residues which are plateletaggregation inhibitors. The application PCT/US90/03788 discloses smallcyclic platelet aggregation inhibitors which are synthetic cyclicpentapeptides containing the tripeptide sequence Arg-Gly-Asp and athioether linkage in the cycle. The application PCT/US90/05367 publishedMay 2, 1991 also discloses the use of peptides and pseudopeptides suchas N-amidino-piperidine-3-carboxylglycyl-L-aspartyl-L-valine thatinhibit platelet aggregation and thrombus formation in mammalian blood.The application Eur. Pat. App. No. 91103462.7 discloses linear compoundswhich can include internal piperazinyl or piperidinyl derivatives. Eur.Pat. App. No. 91300179.8, assigned to Merck & Co., Inc., and publishedon Jul. 17, 1991 discloses linear polypeptide fibrinogen receptorantagonists. Eur. Pat. App. No. 90101404.3 discloses compounds of the R¹-A-(W)_(a) -X-(CH₂)_(b) -(Y)_(c) -B-Z-COOR wherein R¹ is a guandidino oramidino moiety and A and B are chosen from specific monosubstituted arylor heterocyclic moieties.

While a multitude of compounds or peptide analogs believed to inhibitplatelet aggregation by inhibiting binding to a blood platelet byfibrinogen are known, the present invention provides novel fibrinogenreceptor antagonists that have significant binding activity and are,therefore, useful for the reasons stated herein. A number of veryserious diseases and disorders involve hyperthrombotic complicationswhich lead to intravascular thrombi and emboli. Myocardial infarction,stroke, phlebitis and a number of other serious conditions create theneed for novel and effective fibrinogen receptor antagonists.

SUMMARY OF THE INVENTION

The invention is a fibrinogen receptor antagonist of the formula:##STR2## and the pharmaceutically acceptable salts thereof wherein: R¹is chosen independently from

hydrogen,

C₁₋₆ alkyl,

arylC₄₋₁₀ alkyl,

aryl,

carboxy,

C₁₋₆ alkyloxy,

carboxyC₀₋₆ alkyl,

carboxyC₁₋₆ alkyloxy,

hydroxyC₀₋₆ alkyl,

C₁₋₄ alkylsulfonylC₀₋₆ alkyl,

C₀₋₄ alkylaminoC₀₋₆ alkyl,

arylC₀₋₁₀ alkylaminoC₀₋₆ alkyl,

C₂₋₁₀ acylaminoC₀₋₆ alkyl,

C₁₋₄ carboalkoxyC₀₋₆ alkyl, or

halogen;

R² is chosen independently from

H,

halogen,

hydroxy,

C₁₋₆ alkyloxy,

aryl C₀₋₄ alkyl,

aryl C₀₋₆ alkyloxy,

C₁₋₆ alkyl, wherein the alkyl group is unsubstituted or substituted withone or more groups chosen from: (a) hydroxy, (b) C₁₋₄ alkyloxy, (c)amino C₀₋₁₀ alkylcarbonyl, (d) arylC₀₋₁₀ alkylcarbonyl, (e) C₁₋₆alkylcarbonylamino, (f) arylC₀₋₄ alkylcarbonylamino, (g) C₁₋₆alkylsulfonyl, (h) arylC₀₋₆ alkylsulfonyl, (i) C₁₋₆ alkylsulfonylamino,(j) arylC₀₋₁₀ alkylsulfonylamino, (k) C₁₋₁₀ alkyl oxycarbonylamino, (l)arylC₀₋₆ alkylamino, (m) arylC₀₋₆ alkylcarbonylamino, (n) amino, (o)carboxyl, (p) aryl (q) -carbonyl-P or --SO₂ -P where P is a single L orD amino acid or a sequence of 2-4 L or D amino acids connected by amidelinkages.

carboxyl,

C₁₋₆ alkylcarbonyl,

aryl C₀₋₁₀ alkylcarbonyl,

C₁₋₆ alkyloxycarbonylaminoC₁₋₆ alkyl,

C₀₋₆ alkylaminocarbonylaminoC₁₋₆ alkyl,

arylC₀₋₆ alkylaminocarbonylaminoC₁₋₆ alkyl,

aryl C₀₋₆ alkyloxycarbonylaminoC₁₋₆ alkyl

C₁₋₆ alkyloxycarbonyl, or

arylC₀₋₆ alkyloxycarbonyl,

and provided that when there is more than one R² on the same carbonatom, they may be the same or different;

R³ is

H,

C₁₋₆ alkyl, or

arylC₁₋₁₀ alkyl;

Z is

NR⁴ R⁵ wherein R⁴ and R⁵ are independently H, C₁₋₆ alkyl, aryl C₁₋₁₀alkyl wherein said alkyl groups are unsubstituted or substituted withC₁₋₄ alkyloxy, carboxy C₀₋₆ alkyl, hydroxy, halogen, or

a 4-9 membered mono or bicyclic ring system containing 1, 2 or 3heteroatoms chosen from N, O or S and either unsubstituted orsubstituted with R⁴ or R⁵, or ##STR3## Y is C₁₋₁₀ alkyl eitherunsubstituted or substituted with one or more groups selected from R⁴ orR⁵ ;

C₄₋₈ cycloalkyl,

aryl,

C₀₋₃ alkylarylC₀₋₃ alkyl,

C₀₋₃ alkylarylC₀₋₃ alkylcarbonyl,

C₀₋₃ alkylarylC₀₋₃ alkylcarboxamido,

C₀₋₃ alkylaryloxyC₀₋₃ alkyl,

C₀₋₃ alkyloxyC₀₋₆ alkyl, ##STR4## or --(CH₂)_(m) --Q--(CH)_(n) where Qis a C₂₋₈ membered heterocyclic ring containing 1, 2, or 3 heteroatomschosen from N, O or S and substituted or unsubstituted with oxo, thio,or C₁₋₄ alkyl and m and n are chosen from the integers 0, 1, 2, or 3;

X is

O,

S,

SO,

SO₂,

CO,

--NR⁴ CO--,

--CONR⁴ --,

--CH₂ --,

--CH═CH,

--C.tbd.C--,

--NR⁴ CS--,

--CSNR⁴ --,

SO₂ NR⁴, or

NR⁴ SO₂.

A preferred group of compounds of the present invention are thosedefined for the general structure: ##STR5## wherein: R¹ is H,

C₁₋₃ alkyl, or

carboxyC₁₋₃ alkyl;

R² is chosen from:

hydroxy,

halogen,

hydrogen,

arylC₀₋₄ alkyl,

carboxylC₀₋₂ alkyl,

C₁₋₆ alkyloxy carbonyl,

C₁₋₆ alkyl, wherein the alkyl group is unsubstituted or substituted withC₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylamino, C₁₋₆ alkylcarbonyl;arylC₀₋₆ alkylamino, C₁₋₆ alkylcarbonylamino, arylC₀₋₆ alkylsulfonyl,arylC₀₋₆ alkylsulfonylamino, arylC₀₋₆ alkylcarbonyl, or arylC₀₋₆alkylcarbonylamino;

R³ is

H, or

C₁₋₆ alkyl;

Z is

NR⁴ R⁵, or

a 4-9 membered mono or bicyclic ring system containing 1 or 2heteroatoms chosen from N and either unsubstituted or substituted withR⁴ or R⁵, or ##STR6## Y is C₁₋₁₀ alkyl either unsubstituted orsubstituted

with R⁴ or R⁵,

--CH₂ arylCH₂ --,

--CH₂ arylCO--, or

--CH₂ arylOCH₂ --;

X is

--O--,

--S--,

--SO--,

--SO₂ --,

--CO--

--NR⁴ CO--,

--CONR⁴ --,

--CH₂ --,

--CH═CH--, or

--C.tbd.C--.

A more preferred group of compounds of the present invention are thosedefined for the general structure: ##STR7## wherein, R² is chosen from:

hydrogen,

hydroxy,

halogen,

C₁₋₆ alkyloxycarbonyl,

carboxy

C₁₋₆ alkyl, wherein the alkyl group is substituted with

C₁₋₆ alkylsulfonyl,

arylC₀₋₆ alkylsulfonyl,

C₁₋₆ alkylsulfonylamino,

arylC₀₋₆ alkylsulfonylamino,

C₁₋₆ alkylcarbonyl,

arylC₁₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonylamino

arylC₀₋₆ alkylcarbonylamino,

amino, or

aryl;

Z is

NR⁴ R⁵ or

a 5-7 membered monocyclic ring system containing 1 or 2 heteroatomschosen from N and either unsubstituted or substituted with R⁴ or R⁵ ; or##STR8## Y is C₁₋₆ alkyl either unsubstituted or substituted with R⁴ orR⁵ ;

--CH₂ arylCH₂ --, or

--CH₂ arylCO--;

X is

--O--,

--SO₂,

--NR⁴ CO--,

--CONR⁴ --,

--CH₂ --,

--CO--, or

--CH═CH--.

DETAILED DESCRIPTION OF THE INVENTION

The term "pharmaceutically acceptable salts" shall mean non-toxic saltsof the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts include the following salts: Acetate,benzenesulfonate, benzoate, bicarbonate, sisulfate, sitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, valerate.

The term "pharmaceutically effective amount" shall mean that amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system or animal that is being sought by aresearcher or clinician. The term "anti-coagulant" shall includeheparin, and warfarin. The term "thrombolytic agent" shall includestreptokinase and tissue plasminogen activator. The term "plateletanti-aggregation agent" shall include aspirin and dipyridamole.

The term "aryl" shall mean a mono- or polycyclic system composed of 5-and 6-membered aromatic rings containing 0, 1, 2, 3, or 4 heteroatomschosen from N, O or S and either unsubstituted or substituted with R⁴ orR⁵.

The term "alkyl" shall mean straight or branched alkane, alkene oralkyne. The term "alkoxy" shall be taken to include an alkyl portionwhere alkyl is as defined above.

The terms "arylalkyl" and "alkylaryl" shall be taken to include an alkylportion where alkyl is as defined above and to include an aryl portionwhere aryl is as defined above. The C_(0-n) or C_(1-n) designation wheren may be an integer from 1-10 or 2-10 respectively refers to the alkylcomponent of the arylalkyl or alkylaryl unit.

The term "halogen" shall include fluorine, chlorine, iodine and bromine.

The term "oxy" shall mean an oxygen (O) atom. The term "thio" shall meana sulfur (S) atom. Under standard nonmenclature used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionallity toward the pointof attachment. For example, a C₁₋₆ alkyl substituted with C₁₋₆alkylcarbonylamino is equivalent to ##STR9##

In the schemes and examples below, various reagent symbols have thefollowing meanings:

BOC(Boc): t-butyloxycarbonyl.

Pd-C: Palladium on activated carbon catalyst.

DMF: Dimethylformamide.

DMSO: Dimethylsulfoxide.

CBZ: Carbobenzyloxy.

CH₂ Cl₂ : Methylene chloride.

CHCl₃ : chloroform.

EtOH: ethanol.

MeOH: methanol.

EtOAc: ethyl acetate.

HOAc: acetic acid.

BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium,hexafluorophosphate.

EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

Oxone: potassium peroxymonosulfate

LDA: Lithium diisopropylamide

The compounds of the present invention can be administered in such oralforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixers,tinctures, suspensions, syrups, and emulsions. Likewise, they may beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramusculsar form, all using forms well known tothose of ordinary skill in the pharmaceutical arts. An effective butnon-toxic amount of the compound desired can be employed as ananti-aggregation agent.

Compounds of the invention may be administered to patients whereprevention of thrombosis by inhibiting binding of fibrinogen to theplatelet membrane glycoprotein complex IIb/IIIa receptor is desired.They are useful in surgery on peripheral arteries (arterial grafts,carotid endarterectomy) and in cardivascular surgery where manipulationof arteries and organs, and/or the interaction of platelets withartificial surfaces, leads to platelet aggregation and consumption. Theaggregated platelets may form thrombi and thromboemboli. They may beadministered to these surgical patients to prevent the formation ofthrombi and thromboemboli.

Extracorporeal circulation is routinely used for cardiovascular surgeryin order to oxygenate blood. Platelets adhere to surfaces of theextracorporeal circuit. Adhesion is dependent on the interaction betweengpIIb/IIIa on the platelet membranes and fibrinogen adsorbed to thesurface of the circuit. (Gluszko et al., Amer. J. Physiol., 252(H),615-621 (1987)). Platelets released from artificial surfaces showimpaired hemostatic function. Compounds of the invention may beadministered to prevent adhesion.

Other applications of these compounds include prevention of plateletthrombosis, thromboembolism and reocclusion during and afterthrombolytic therapy and prevention of platelet thrombosis,thromboembolism and reocclusion after angioplasty or coronary and otherarteries and after coronary artery bypass procedures. They may also beused to prevent myocardial infarction.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarilly skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter, or arrest the progress of thecondition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 100 mg/kg/day and preferably 1.0-100 mg/kg/day andmost preferably 1-20 mg/kg/day. Intravenously, the most preferred doseswill range from about 1 to about 10 mg/kg/minute during a constant rateinfusion. Advantageously, compounds of the present invention may beadministered in divided doses of two, three, or four times daily.Furthermore, preferred compounds for the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using those forms of transdermalskin patches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, or course, be continuous rather that intermittantthroughout the dosage regime.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as "carrier" materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixers, syrups and the like, andconsistent with convention pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium sterate, dicalciumphosphate, calcium sulfate, mannitol, sorbitol and the like; for oraladministration in liquid form, the oral drug components can be combinedwith any oral, non-toxic, pharmaceutically acceptable inert carrier suchas ethanol, glycerol, water and the like. Moreover, when desired ornecessary, suitable binders, lubricants, distintergrating agents andcoloring agents can also be incorporated into the mixture. Suitablebinders include starch, gelatin, natural sugars such as glucose orbeta-lactose, corn-sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylkcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium sterate, magnesium sterate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch methyl cellulose, agar, bentonite,xanthan gum and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug cariers. Suchpolymers can include polyvinlypyrrolidone, pyran copolymer,polyhydroxypropyl-methacrylamide-phenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels.

The compounds of the present invention can also be co-administered withsuitable anti-coagulation agents or thrombolytic agents such asplasminogen activators or streptokinase to achieve synergystic effectsin the treatment of various vascular pathologies. They may also becombined with heparin, aspirin, or warfarin.

The novel compounds of the present invention were prepared according tothe procedure of the following schemes and examples, using appropriatematerials and are further exemplified by the following specificexamples. The most preferred compounds of the invention are any or allof those specifically set forth in these examples. These compounds arenot, however, to be construed as forming the only genus that isconsidered as the invention, and any combination of the compounds ortheir moieties may itself form a genus. The following examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds. All temperatures aredegrees Celcius unless otherwise noted.

In addition to the following preparative procedures, several examples ofin-vitro bioactivity of compounds within the scope of the presentinvention are indicated. To illustrate, one test which is used toevaluate fibrinogen receptor antagonist activity is based on evaluationof inhibition of ADP-stimulated platelets. Aggregation requires thatfibrinogen bind to and occupy the platelet fibrinogen receptor site.Inhibitors of fibrinogen binding inhibit aggregation. In theADP-stimulated platelet aggregation assay used to determine inhibitionassociated with the compounds claimed in the instant invention, humanplatelets are isolated from fresh blood, collected into acidcitrate/dextrose by differential centrifugation followed by gelfiltration on Sepharose 2 B in divalent ion-free Tyrode's buffer (pH7.4) containing 2% bovine serum albumin.

Platelet aggregation is measured at 37° C. in a Chronolog aggregometer.The reaction mixture contains gel-filtered human platelets (2×10⁸ perml), fibrinogen (100 micrograms per ml (ug/ml)), Ca²⁺ (1 mM), and thecompound to be tested. The aggregation is initiated by adding 10 μM ADP1 minute after the other components are added. The reaction is thenallowed to proceed for at least 2 minutes. The extent of inhibition ofaggregation is expressed as the percentage of the rate of aggregationobserved in the absence of inhibitor. The IC₅₀ is the dose of aparticular compound inhibiting aggregation by 50% relative to a controllacking the compound.

Synthesis of Novel Fibrinogen Receptor Antagonists:

Compounds useful as fibrinogen receptor antagonists may be preparedaccording to the general scheme depicted in Scheme 1.

In general terms, a halophenol (1-1) is reacted with sodium hydride andthe resulting sodium salt is treated with theBOC-protected-4-piperidinyl butylbromide derivative(1-2) to yield anether derivative(1-3). This product is subsequently reacted with n-butyllithium and tributyl tin chloride to yield the stannaneintermediate(1-4). This product is then reacted with 2-bromomethylacrylate to yield the 1,4-substituted aromatic piperidinyl derivative(1-5). n-Butyl mercaptan is then added to the activated double bond toyield the sulfur substituted compound (1-6) which is subsequentlyoxidized to the sulfone (1-7). Deprotection of the carboxyl andpiperidine groups then provides the sulfone acid (1-8). ##STR10##

Compounds claimed in the instant invention and depicted in the followingformula: ##STR11## can readily be prepared according to this generalscheme by substituting or replacing the various reagents in Scheme 1.

For example, a trisubstituted 4-halophenol derivative wherein the 3rdsubstituent (R¹) may be C₁₋₆ alkyl, arylC₁₋₁₀ alkyl, aryl, carboxy, C₁₋₆alkyloxy, carboxyC₁₋₆ alkyl, carboxyC₁₋₆ alkyloxy, hydroxyC₁₋₆ alkyl,C₁₋₄ alkylsulfonylC₁₋₆ alkyl, C₀₋₄ alkylaminoC₁₋₆ alkyl, C₀₋₁₀arylalkylaminoC₁₋₆ alkyl, C₂₋₁₀ acylamino, C₁₋₆ alkyl, C₁₋₄carboalkoxyC₁₋₆ alkyl or halogen may be used as the initial reactant. A4-halophenol compound or a trisubstituted (R¹) derivative may then bereacted with (1-2) or another suitably substituted alkyl halide to yielda compound of the general formula (II): ##STR12## wherein Z-Y-hal is asuitably substituted alkyl halide and Z is chosen from amines orsubstituted amines such as NR⁴ R⁵ wherein R⁴ and R⁵ are independently H,C₁₋₆ alkyl, arylC₁₋₁₀ alkyl wherein the alkyl groups may beunsubstituted or substituted with C₁₋₄ alkyloxy, carboxyC₀₋₆ alkyl,hydroxy, or halogen. Z may also be a 4-9 membered mono or bicyclic ringsystem containing 1, 2 or 3 heteroatoms chosen from N, O or S and eitherunsubstituted or substituted with R⁴ or R⁵. In addition Z may be##STR13## The Y component which is covalently bonded to Z may be C₁₋₁₀alkyl either unsubstituted or substituted with one or more groupsselected from R⁴ or R⁵, C₄₋₈ cycloalkyl, C₀₋₃ alkylarylC₀₋₃ alkyl, C₀₋₃alkylarylC₀₋₃ alkylcarbonyl, C₀₋₃ alkylarylC₀₋₃ alkylcarboxamido, C₀₋₃alkylaryloxyC₀₋₃ alkyl, C₀₋₃ alkyloxyC₀₋₆ alkyl, ##STR14## where Q is aC₂₋₈ heterocyclic ring containing 1, 2 or 3 heteratoms chosen from N, O,or S and substituted or unsubstituted with oxo, thio, or C₁₋₄ alkyl andm and n are chosen from the integers 0, 1, 2, or 3; or aryl. The Yconstituent contains the reactive halide which is amenable tosubstitution by a nucleophilic di- or trisubstituted 4-halophenolcompound.

The generic compound depicted in formula (II) may then be reacted withn-butyl lithium and a trisubstituted tin chloride to yield 1-4 or othersuitable stannane intermediate. This is then reacted with 2-bromomethylacrylate to yield a compound of the general formula (III): ##STR15## 1-5is a representative example of a compound within the structure depictedin formula (III). The compounds within formula (III) contain anactivated double bond which is amenable to further elaboration. Forexample, n-butyl mercaptan or other suitable reagents such as: sodiummethoxide, benzyl mercaptan, benzylamine, or other suitable amine can bereacted with (III) to form a compound with the general formula (IV)wherein the R^(2') group represents the nucleophile. If R^(2') is analkyl or benzyl mercaptan group it can be further oxidized to thesulfone or sulfoxide derivative. If R^(2') is a benzylamine, afteraddition to the activated double bond it can be reduced to the freeamine and further reacted with benzoyl chloride, alkylsulfonyl chlorideor arylC₀₋₁₀ alkylsulfonyl chloride to yield compounds of the claimedinvention. ##STR16##

The methyl ester group of IV may readily be substituted with anotherC₁₋₆ alkyl constituent, an arylC₁₋₁₀ alkyl constituent, or hydrogen toyield compounds of the general formula (V): ##STR17##

EXAMPLE 1 ##STR18##4-[4-(N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]-bromobenzene (1-3)

A solution of 1-1(2.0 g, 11.43 mmoles) in 20 ml DMF was added at 0°-5°C. to sodium hydride (NaH) (0.27 g, 11.5 mmoles) suspended in DMF (10ml) and this was stirred for 1 hour to give a clear, dark solution.4-(4-N-t-butyloxycarbonylpiperidinyl)butyl bromide (1-2) (3.68 g, 11.5mmoles) in 4 ml DMF was then added dropwise at 0°-10° C. with stirring.1-2 was prepared by first reacting 4-piperidine-2-ethanol (availablefrom American Tokyo Kasec) (130 g, 1.0 mole) with 3N NaOH (336 mL, 1.0mole) at 0° C. and di-t-butylcarbonate (221.8 g, 1.0 mole). ThisBoc-protected piperidine (102.5 g, 0.45 m) was then reacted with oxaylchloride (55.8 ml, 0.64 mole); DMSO (54.2 ml, 0.76 mole) and NEt₃ (213ml, 1.53 mole). The resultant aldehyde was reacted withcarbomethoxytriphenylphosphorane (179 g, 0.536 mole) to give a transmethyl ester which was reduced (H₂ /Pd), hydrolyzed (NaOH), reduced(BH₃) and brominated (C₆ H₅)₃ P, CBr₄) to give (1-2). The reactionbetween 1-1 and 1-2 was allowed to proceed for 16 hours as thetemperature slowly rose to ambient temperature or 25° C. The solvent wasremoved under vaccum at less than 30° C. and the resultant residue wastaken up in 10% aqueous potassium hydrogen sulfate (KHSO₄) solution (500ml) and extracted with ether (Et₂ O). The ether extract was washed withH₂ O, and brine, and then dried with sodium sulfate (Na₂ SO₄). Thesolvent was then removed. The residue was purified by flashchromatography on silica gel eluting with hexane/ethyl acetate (EtOAc)in a 11/2 ratio to yield pure 1-3 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ1.04(2H,m), 1.20-1.42 (3H,m), 1.47 (9H,s),1.68 (2H,d), 1.76 (2H,m), 2.68 (2H,t), 3.91 (2H,t), 4.09(2H,m), 6.77(2H,d), 7.36 (2H,d).

EXAMPLE 2 ##STR19##4-[4-(N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]-phenyltributylstannane (1-4)

A solution of 1-3 (6.97 g, 17.5 mmoles) in THF (150 ml) was cooled to-75° C. and treated with n-butyl lithium (n-BuLi)(17.5 mmoles) dropwise.After stirring at -70° C. for 1 hr, tributyltin chloride (5.70 g, 17.5mmol) was added dropwise. This was stirred at -70° C. for 2 hours andthen overnight as the temperature was allowed to rise to ambienttemperature. The solvent was subsequently removed and the residue wastaken up in ether (500 ml), washed with H₂ O and brine, and dried withNa₂ SO₄. Solvent removal gave 1-4 as a viscous oil.

¹ H NMR (300 MHz, CDCl₃) δ0.88 (9H, t), 1.0-1.15 (8H, m), 1.26-1.40 (6H,m), 1.47 (9H, s), 1.48-1.55 (6H, m), 1.65 (2H, m), 1.78 (2H, m), 2.67(2H, bt), 3.94 (2H, t), 4.06 (2H, m), 6.99 (2H, d), 7.35 (2H, d).

EXAMPLE 3 ##STR20## Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]phenylmethylpropenoate (1-5)

To a solution of bis(dibenzylideneacetone) palladium (0.03 g, 0.067mmoles) in tetrahydrofuran (THF) (5 ml) was added triphenylphosphine(0.035 g, 0.134 mmoles), followed by addition of methyl-2-bromomethylacrylate (0.40 g, 2.24 mmol) and 1-4 (1.48 g, 2.24 mmoles). The reactionsolution was flushed with nitrogen (N₂), stoppered, and heated at 50° C.for 48 hours. The cooled reaction mixture was then poured into a mixtureof ether (100 ml) and water (100 ml) containing 1.5 g of sodium floride(NaF). The organic phase was washed with brine, dried (Na₂ SO₄) and thesolvent removed. The residue was purified by flash chromatography onsilica gel eluting with hexane/EtOAc in a 9/1 ratio to give pure 1-5.

¹ H NMR (300 MHz, CDCl₃) δ1.10 (2H, m), 1.24-1.40 (4H, m), 1.45 (9H, s),1,65 (2H, m), 1.74 (2H, m), 2,68 (2H, bt), 3.68 (3H, s), 3.73 (3H, s),3.92 (2H, t), 4.07 (2H, m), 5.93 (1H, m), 6.20 (1H, m), 6.80 (2H, d),7.09 (2H, d).

EXAMPLE 4 ##STR21## Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]phenylmethyl-3-(n-butylthio)propanoate(1-6)

To a solution of 1-5 (0.302 g, 0.7 mmmoles) in MeOH (8 ml) was addedn-butylmercaptan (0.063 g, 0.7 mmoles) at 0°-5° followed by a catalyticamount of NaH. This was stirred at 0°-5° for 1 hour and then at roomtemperature for 16 hours.

The solvent was removed in vacuo to give 1-6 as a viscous oil.

¹ H NMR (300 MHz, CDCl₃) δ0.90 (3H, t), 1.09 (2H, m), 1.34-1.45 (3H, m),1.46 (9H, s), 1.51 (2H, m), 1.66 (2H, d), 1.75 (2H, m), 2.49 (2H, t),2.60-2095 (8H, m), 3.64 (3H, s), 3.92 (2H, t), 4.07 (2H, m), 6.70 (2H,d), 7.06 (2H, d).

EXAMPLE 5 ##STR22## Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]phenylmethyl-3-(n-butylsulfonyl)propanoate(1-7)

A solution of 1-6 (0.7 mmoles) in MeOH (8 ml) was treated with 1.5 ml 2NH₂ SO₄ solution at 0°-10° and then oxone (1.29 g, 21.0 mmoles) was addedat 0°-10°. The resulting solution was stirred for 16 hours.

The reaction was diluted with 100 ml H₂ O and extracted in CH₂ Cl₂. Theorganic extract was washed with brine, dried (Na₂ SO₄) and the solventwas removed. The residue was purified by flash chromtography on silicagel eluting with hexane/EtOAc (7:3) to give 1-7 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ0.92 (3H, t), 1.11 (2H, m), 1.13-1.45 (3H, m),1.46 (9H, s), 1.62-182 (4H, m), 2.67 (2H, bt), 2.80-3.12 (5H, m), 3.29(1H, m), 3.45 (1H, m), 3.70 (3H, s), 3.92 (2H, t), 4.08 (3H, m).

EXAMPLE 6 ##STR23##2-[4-(4-Piperidin-4-yl)butyloxy]phenylmethyl-3-(n-butylsulfonyl)propanoicacid (1-8)

A solution of 1-7 (0.31 g, 0.56 mmoles) in THF/MeOH/H₂ O 1:1:1 (15 ml)was treated with LiOH.H₂ O (0.067 g, 1.6 mmoles) at room temperature for16 hours. The reaction mixture was then diluted with H₂ O (100 ml),acidified with 10% KHSO₄ solution and extracted with EtOAc. The organicextract was washed in brine, dried (Na₂ SO₄) and the solvent removed.The residue was purified by flash chromatography on silica gel elutingwith CHCl₃ /MeOH/HOAc 97:3:1 to give the desired acid.

¹ H NMR (300 MHz, CDCl₃) δ0.91 (3H, t), 1.08 (2H, m), 1.25-1.4 (3H, m),1.47 (9H, s), 1.67 (3H, m), 1.75 (3H, m), 2.66 (2H, bt), 2.85-3.00 (3H,m), 3.13 (1H, dd), 3.32 (1H, m), 3.45 (1H, m), 3.92 (2H, t), 4.03 (2H,m), 6.82 (2H, d), 7.01 (2H, d).

This acid (0.058 g) was dissolved in EtOAc (30 ml) and the solution wascooled to -30° and treated with HCl for 0.5 hour. The flask was thenstoppered and the contents stirred at 0° for 1 hour.

The solvent was removed and the residue triturated with Et₂ O to givepure 1-8.

¹ H NMR (300 MHz, CD₃ OD) δ0.94 (3H, t), 1.40 (4H, m), 1.50-1.81 (4H,m), 1.95 (2H, bd), 2.84 (1H, m), 3.00 (4H, m), 3.16 (1H, m), 3.30 (2H,m), 3.35 (2H, bd), 3.52 (1H, m), 3.96 (2H, t), 6.85 (2H, d), 7.15 (2H,d).

EXAMPLE 7 ##STR24## Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]phenylmethyl-3-(benzylthio)propanoate(1-9)

1-5 (0.432 g, 1.0 mmoles) was treated with benzylmercaptan (0.124 g, 1.0mmole) as described for 1-6. Crude 1-9 had R_(f) 0.45, silica gel,hexane/EtOAc (8:2).

EXAMPLE 8 ##STR25## Methyl2-[4-(4-Piperidin-4-yl)butyloxy]phenylmethyl-3-(benzylsulfonyl)propanoate(1-10)

A methanol solution (10 ml) of 1-9 (1.0 mmoles) was acidified at 0°-5°with 2 drops 2N H₂ SO₄ solution and then oxone (3.0 mmoles) was added at0°-5° with stirring. After 24 hours stirring the reaction mixture wasdiluted with H₂ O and extracted with CH₂ Cl₂. The organic extract waswashed in H₂ O, brine, dried (Na₂ SO₄) and the solvent removed. Theresidue was purified by flash chromatography on silica gel eluting withhexane/EtOAc (75:25) to give pure 1-10 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ1.10 (2H, m), 1.25-1.45 (3H, m), 1.47 (9H, s),1.65 (2H, d), 1.74 (2H, m), 2.61-2.92 (5H, m), 3.00 (1H, m), 3.21 (1H,m), 3.36 (1H, m), 3.70 (3H, s), 3.92 (2H, t), 4.06 (2H, m), 4.17 (2H,d), 6.70 (2H, d), 6.97 (2H, d), 7.25-7.40 (5H, m).

EXAMPLE 9 ##STR26##2-[4-(4-N-piperidin-4-ylbutyloxy]phenylmethyl]-3-(benzylsulfonyl)propanoicacid (1-11)

1-10 (0.2 g, 0.34 mmoles) was hydrolyzed with LiOH.H₂ O (0.015 g, 0.35mmoles) as described for 1-8 to provide the desired acid, R_(f) 0.35(silica gel, CHCl₃ /MeOH/HOAc (97:3:1).

¹ H NMR (300 MHz, CDCl₃) δ1.09 (2H, m), 1.25-1.45 (4H, m), 1.47 (9H, s),1.65 (2H, d), 1.74 (2H, m), 2.64 (2H, bt), 2.78-2.95 (2H, m), 3.06 (1H,m), 3.12 (1H, m), 3.35 (1H, m), 3.92 (2H, t), 4.03 (2H, m), 0.419 (2H,s), 6.80 (2H, d), 7.02 (2H, d), 7.28 (2H, m), 7.35 (3H, m).

This acid was treated with HCl as described for 1-8 to provide crude1-11. This was triturated to give 1-11 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ1.36 (4H, m), 1.56 (3H, m), 1.76 (2H, m),1.95 (2H, d), 2.81 (1H, m) 2,97 (4H, m), 3.15 (1H, bs), 3.36 (4H, m),3.97 (2H, t), 4.34 (2H, s), 6.82 (2H, d), 7.07 (2H, d), 7.23 (5H, m).

EXAMPLE 10 ##STR27## Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]phenylmethyl-3-(benzylamino)propanoate(1-12)

A solution of 1-5 (0.216 g, 0.5 mmoles) in toluene (8 ml) was treatedwith benzylamine (10 mmoles) and the resulting solution was heated at100° for 16 hrs.

The reaction was diluted with EtOAC (100 ml) and this was washed with10% KHSO₄ solution, H₂ O, brine, and dried (Na₂ SO₄). Solvent removalgave an oil that was purified by flash chromatography on silica geleluting in CHCl₃ /MeOH (98:2) to give 1-12 as an oil, R_(f) 0.35 (silicagel, hexane/acetone (8:2).

¹ H NMR (300 MHz, CDCl₃) δ1.09 (4H, m) 1.25-1.45 (4H, m), 1.47 (9H, s),1.67 (2H, d), 1.76 (2H, m), 2.63-2.95 (8H, m), 3.63 (3H, s), 3.77 (1H,d), 3.91 (2H, t), 4.06 (2H, m), 6.76 (2H, d), 7.02 (2H, d), 7.23 (5H,m).

EXAMPLE 11 ##STR28##2-[4-(4-Piperidin-4-yl)butyloxy]phenylmethyl-3-(benzylamino)propanoicacid (1-13)

1-12(0.23 g, 0.43 mmoles) was treated with LiOH.H₂ O (0.03 g, 0715mmoles) as described for 1-8 to give the desired acid (1-13).

¹ H NMR (300 MHz, CD₃ OD) δ1.09 (2H, m) 1.34 (2H, m), 1.45 (9H, s), 1.51(2H, m), 1.65-1.80 (4H, m), 2.72 (3H, m), 2.93 (2H, m), 3.10 (2H, m),3.92 (2H, t), 4.05 (2H, d), 4.16 (2H, d), 6.81 (2H, d), 7.09 (2H, d),7.40 (4H, m).

This acid was dissolved in EtOAc and treated with HCL gas as describedfor 1-8 to give 1-13 as a white solid after trituration with Et₂ O.

¹ H NMR (300 MHz, CD₃ OD) δ1.40 (4H, m) 1.45-1.65 (3H, m), 1.69 (2H, m),1.97 (2H, bd), 2.80 (1H, m), 3.00 (6H, m), 3.19 (1H, m), 3.35 (3H, m),3.93 (2H, m), 4.18 (2H, m), 6.81 (2H, d), 7.08 (2H, d), 7.39 (5H, m).

EXAMPLE 12 ##STR29## Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]phenylmethyl-3-(amino)propanoate(1-13)

A solution of 1-12 (0.80 g) in EtOH (30 ml) was treated with Pd(OH)₂ /C(1.0 g) and this suspension was hydrogenated at atmospheric pressure.After 16 hours the solvent was removed and the residue was purified byflash chromatography on silica gel eluting with CHCl₃ /MeOH(95:5) togive pure 1-14.

¹ H NMR (300 MHz, CDCl₃) δ1.09 (2H, m) 1.23-1.44 (3H, m), 1.47 (9H, s),1.65 (2H, d), 1.73 (2H, m), 2.15 (2H, bs), 2.59-2.80 (4H, m), 3.90 (2H,m), 3.65 (3H, s), 3.91 (2H, t), 4.04 (2H, m), 6.78 (2H, d), 7.06 (2H,d).

EXAMPLE 13 ##STR30## Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]phenylmethyl-3-(benzoylamino)propanoate(1-13)

A solution of 1-14 (0.2 g 0.45 mmoles) in CH₂ Cl₂ at 0°-5° was treatedwith triethylamine (0.068 g, 0.67 mmoles) followed by benzoylchloride(0.07 g, 0.5 mmoles) and the resulting mixture was stirred at roomtemperature for 16 hours.

The solvent was removed and the residue was taken up in Et₂ O (125 ml)and this was washed with H₂ O, brine and dried (Na₂ SO₄). Solventremoval gave a residue that was purified by flash chromatography onsilica gel eluting with hexane/acetone (75:25) to give pure 1-15.

1H NMR (300 MHz, CDCl₃) δ1.09 (2H, m) 1.22-1.45 (3H, m), 1.49 (9H, s),1.68 (2H, d), 1.74 (2H, m), 1.81 (2H, bs), 2.57 (2H, dt), 2.84 (1H, m),3.00 (1H, m), 3.58 (1H, m), 3.68 (3H, s), 3.90 (2H, t), 4.07 (2H, d),6.80 (2H, d), 7.10 (2H, d), 7.41 (3H, m), 7.70 (2H, m).

EXAMPLE 14 ##STR31##2-[4-(4-Piperidin-4-yl)butyloxy]phenylmethyl-3-(benzoylamino)propanoicacid (1-16)

1-15 (0.19 g 3.44 mmoles) was hydrolyzed with LiOH.H₂ O as described for1-8 to give the desired acid.

¹ H NMR (300 MHz, CDCl₃) δ1.06 (2H, m) 1.25-1.45 (3H, m), 1.47 (9H, s),1.63 (2H, d), 1.73 (2H, m), 2.65 (2H, bt), 2.84 (1H, m), 3.03 (2H, m),3.58 (1H, m), 3.73 (1H, m), 3.90 (2H, t), 4.03 (2H, bd), 6.80 (2H, d),7.12 (2H, d), 7.40 (3H, m), 7.69 (2H, d).

This acid was treated with HCl gas in EtOAc as described for 1-8 to give1-16 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ1.03-1.18 (2H, m) 1.22-1.53 (5H, m), 1.70(2H, m), 2.52 (2H, m), 2.64-2.81 (2H, m), 2.95 (2H, m), 3.91 (2H, t),6.78 (2H, d), 7.14 (2H, d), 7.44 (3H, m), 7.74 (2H, d).

EXAMPLE 15 ##STR32## Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxy]phenylmethyl-3-(n-butylsulfonylamino)propanoate(1-17)

A solution of 1-14 (0.2 g, 0.45 mmoles) in acetonitrile (10 ml) wastreated with butanesulfonyl chloride (0.078 g, 0.5 mmoles) and pyridine(0.053 g, 0.67 mmoles) and the resulting solution stirred at roomtemperature for 8 hours.

The solvent was removed and the residue was taken up in EtOAc (110 ml),washed with H₂ O, 10% KHSO₄ solution, brine and dried (Na₂ SO₄). Solventremoval gave a residue that was purified by flash chromatography onsilica gel eluting with hexane/EtOAc (75:25) to give pure 1-17 as anoil.

¹ H NMR (300 MHz, CDCl₃) δ0.94 (3H, m) 1.20 (2H, m), 1.36 (3H, m), 1.49(9H, s), 1.60-1.82 (7H, m), 2.68 (2H, bt), 2.80 (1H, m), 2.95 (4H, m),3.23 (1H, t), 3.70 (3H, s), 3.92 (2H, m), 4.05 (2H, bd), 4.66 (1H, m),6.82 (2H, d), 7.07 (2H, d).

EXAMPLE 16 ##STR33##2-[4-(4-Piperindin-4-yl)butyloxy]phenylmethyl-3-(n-butylsulfonylamino)propanoicacid (1-18)

1-17 (0.13 g 0.23 mmoles) was hydrolyzed with LiOH.H₂ O (0.029 g, 0.69mmoles) as described for 1-8 to give the desired acid, R_(f) 0.3 (silicagel, CHCl₃ /MeOH/HOAc (97:3:1).

¹ H NMR (300 MHz, CDCl₃) δ0.96 (3H, t) 1.08 (2H, m), 1.22-1.42 (4H, m),1.46 (9H, s), 1.65 (2H, bd), 1.74 (2H, m), 2.65 (2H, bt), 2.80 (1H, m),2.96 (4H, m), 3.91 (2H, t), 4.05 (2H, m), 5.51 (1H, t), 6.81 (2H, d),7.09 (2H, d).

This acid was treated with HCl gas in EtOAc as described for 1-8 to give1-18 as a white solid, R_(f) 0.4 (silica gel, EtOH/NH₄ OH/H₂ O (9:1:1).

¹ H NMR (300 MHz, CD₃ OD) δ0.96 (3H, t) 1.27-1.58 (9H, m), 1.59-1.80(6H, m), 1.95 (2H, bd), 2.80 (2H, m), 2.85-3.03 (4H, m), 3.10-3.40 (4H,m), 3.93 (2H, t), 6.80 (2H, d), 7.21 (2H, d).

Compounds useful as fibrinogen receptor antagonists may also be preparedaccording to the general scheme depicted in Scheme 2. In general terms,a 4-substituted phenolic ester (2-1) is treated with sodium hydride andreacted with an alkyl halide to yield the 1,4-aromatic derivative (2-2).This compound is benzylated to yield 2-3 and deprotected to give thefree amine 2-4. ##STR34##

Compounds claimed in the instant invention and depicted in the formula:##STR35## can readily be prepared according to the general proceduredescribed in Scheme 2 by substituting or replacing the various reagentsor reactants depending upon the target compound desired.

For example, a trisubstituted 4-substituted phenolic ester may beutilized as the starting reagent in the overall scheme: ##STR36## R¹ isidentical to that described in the Scheme 1 discussion. This compound orthe disubstituted derivative may then be reacted with 1-2 or anothersuitably substituted alkyl halide to yield a compound of the generalformula: ##STR37## wherein Z-Y-hal is a suitably substituted alkylhalide and Z is chosen from the groups described following the Scheme 1discussion. The 1,4-substituted aromatic derivatives may then be treatedwith sodium hydride to produce an enolate which is then reacted with asuitable alkyl halide, arylalkyl halide, activated carbonyl compound(such as dimethylcarbonate) or other suitable electrophilic reagent toyield a compound with the general formula: ##STR38## wherein R² may behydroxy, arylC₁₋₁₀ alkyl, or C₁₋₆ alkyl, wherein the alkyl group isunsubstituted or substituted with amino C₁₋₁₀ alkylcarbonyl or arylC₁₋₁₀alkylcarbonyl. R² may also be carboxyl, C₁₋₆ alkyloxycarbonyl, C₁₋₆alkylcarbonyl, or C₁₋₁₀ arylalkyl carbonyl.

EXAMPLE 17 ##STR39## Methyl3-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoate(2-2)

A solution of methyl 3-(4-hydroxyphenyl)propanoate (2-1) (prepared fromthe corresponding free acid by treatment with diazomethane) (2.06 g,0.0114 moles) in DMF (65 ml) was treated with Cs₂ CO₃ (1.86 g, 0.0057moles) at room temperature with stirring for 15 minutes. To this wasadded a solution of 4-(N-t-butyloxycarbonylpiperidin-4-yl)butyl bromide(3.66 g, 0.00114 moles) dropwise at room temperature and this was heatedat 75° for 16 hours.

The solvent was removed and the residue taken up in H₂ O (100 ml) andextracted with EtOAc. The organic phase was washed with H₂ O, brine,dried (Na₂ SO₄) and the solvent removed. The residue was purified byflash chromatography on silica gel eluting with hexane/EtOAc (85:15) togive pure 2-2 as an oil, R_(f) 0.5.

¹ H NMR (300 MHz, CDCl₃) δ1.08 (2H, m) 1.22-1.41 (4H, m), 1.45 (9H, s),1.65 (2H, bd), 1.76 (2H, m), 1.74 (2H, m), 2.65 (2H, bt), 2.80 (1H, m),2.96 (4H, m), 3.91 (2H, t), 4.05 (2H, m), 5.51 (1H, t), 6.81 (2H, d),7.09 (2H, d).

EXAMPLE 18 ##STR40## Methyl3-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]-2-(benzyl)propanoate(2-3)

Diisopropylamine (0.202 g, 2.0 mmoles) in THF (20 ml) was cooled to 0°and treated with n-butyllithium (2.0 mmoles) and the resulting solutionstirred at 0° for 0.5 hr. After cooling to -70°, the reaction mixturewas treated with 2-2 and stirred for 45 minutes. Then, HMPA (0.18 g, 1.0mmoles) was added followed by benzyl bromide (0.342 g, 2.0 mmoles) andthe reaction mixture was stirred at -70° for 3 hours and then at roomtemperature for 16 hours.

The reaction was quenched with H₂ O (5 ml), the solvent removed and theresidue was taken up in EtoAc, washed with 10% KHSO₄ solution, brine anddried (Na₂ SO₄). Solvent was removed and the residue purified by flashchromatography on silica gel eluting with hexane/EtOAc (85:15) to givepure 2-3, R_(f) 0.35.

¹ H NMR (300 MHz, CDCl₃) δ1.09 (2H, m), 1.23-7.42 (4H,m), 1.46(9H,s),1.65(2H,bd), 1.74(2H,m), 2.59-2.82(4H,m), 2.84-3.03(3H,m), 3.47(3H,s),3.90(2H,t), 4.07(2H,bd), 6.78(2H,d), 7.03(2H,d), 7.05-7.30(5H,m).

EXAMPLE 19 ##STR41##3-[4-(4-Piperidin-4-yl)butyloxyphenyl]-2-(benzyl)propanoic acid (2-4)

2-3 (0.32 g, 0.628 mmoles) was hydrolyzed with LiOH.H₂ O (0.07 g,1.88mmoles) as described for 1-8 to give the desired acid, R_(f) 0.45(silica gel, CHCl₃ /MeOH/HOAc (97:3:1).

¹ H NMR (300 MHz, CDCl₃) δ1.08(2H,m), 1.21-1.40(4H,m), 1.45(9H,s),1.63(2H,bd), 1.75(2H,m), 2.56-2.81(4H,m), 2.85-3.05(3H,m), 3.90(2H,t),4.04(2H,m), 6.78(2H,d), 7.06(2H,d), 7.13-7.30(5H,m).

This acid was dissolved in EtOAc and treated with HCl gas as describedfor 1-8 to give pure 2-4 as a white solid, R_(f) 0.5 (silica gel,EtOH/NH₄ OH/H₂ O (9:1:1).

¹ H NMR (300 MHz, CD₃ OD) δ1.28-1.47(4H,m), 1.48-1.68(3H,m), 1.75(2H,m),1.95(2H,bd), 2.69-2.80(2H,m), 2.80-3.00(5H,m), 3.35(3H,m), 3.91(2H,t),6.80(2N,d), 7.07(2H,d), 7.13-7.27(5H,m).

EXAMPLE 20 ##STR42## Methyl2-Carbomethoxy-3-[4-(4-N-t-Butoxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoate(2-5)

A solution of diisopropylamine (0.202 g, 2.0 mmoles) in THF (20 ml) wascooled to 0° and treated with n-butyllithium (2.0 mmoles) followed bystirring for 0.5 hr. This was then cooled to -70° and 2-2 (0.42 g, 1.0mmoles) in THF (5 ml) was added and the pale yellow solution stirred for1.0 hr. Then, HMPA (0.179 g, 1.0 mmoles) was added followed bydimethylcarbonate (0.18 g, 2.0 mmoles) and the resulting solution wasstirred at -70° for 3 hours and then at room temperature for 12 hours.

The reaction was quenched with H₂ O (3 ml) and diluted with EtOAc and10% KHSO₄ solution, organic phase was washed with 10% KHSO₄ solution,brine, dried (Na₂ SO₄) and the solvent removed. The residue was purifiedby flash chromotography on silica gel eluting with hexane/EtOAc (8:2) togive pure 2-5 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ1.10(2H,m), 1.18-1.40(3H,m), 1.47(9H,S),2.66(2H,d), 2.74(2H,m), 2.68(2H,bt), 3.16(2H,d), 3.64(1H,t), 3.70(3H,S),3.91(2H,t), 4.08(2H,m), 6.80(2H,d), 7.10(2H,d).

2-Carboxy-3-[4-(4-Piperidin-4-yl)butyloxyphenyl]propanoic acid (2-6).

2-5 (0.164 g, 0.343 mmoles) was hydrolyzed with LiOH.H₂ O (0.072 g, 1.72mmoles) as described for 1-8 to give the desired acid as an oil.

¹ H NMR (300 MHz, CDCl₃) δ1.07 (2H,m), 1.21-1.38(4H,m), 1.45(9H,S),1.64(2H,d), 1.73(2H,m), 2.62(2H,bd), 3.89(2H,t), 4.03(2H,m), 6.87(2H,d),7.10(2H,d).

This acid was dissolved in EtOAc and treated with HCl gas as describedfor 1-9 to give pure 2-6 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ1.28-1.43(4H,m), 1.45-1.70(3H,m), 1.85(2H,m),1.94(2H,t), 3.07(2H,d), 3.33(2H,m), 3.53(1H,t), 3.92(2H,t), 6.80(2H,d),7.12(2H,d).

EXAMPLE 21 ##STR43## Methyl2-(Benzyloxycarbonyl)-3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoate(2-7).

2-2 (0.42 g, 1.0 mmoles) in 5 ml THF was added to a THF solution oflithium diisopropylamide (2.0 mmoles) at 0° with stirring continued for0.5 hour. This was cooled to -70° and treated with benzyl chloroformate(0.375 g, 2.2 mmoles and the resulting mixture was stirred at -70° for 3hours and then at room temperature for 12 hours.

The reaction mixture was diluted with 10% KHSO₄ solution and extractedwith Et₂ O. The ether phase was washed with 10% KHSO₄ solution, brine,dried (Na₂ SO₄) and the solvent removed. The residue was purified byflash chromatography on silica gel eluting with hexane/EtOAc (85:15) togive pure 2-7 as an oil. R_(f) 0.45, silica gel, hexane/EtOAc (80:20).

¹ H NMR (300 MHz, CDCl₃) δ1.10(2H,m), 1.23-1.42 4H(m), 1.46(9H,S),1.66(2H,bd), 1.75(2H,m), 2.67(2H,dt), 3.18(2H,d), 3.68(3H,S),3.80(2H,t), 4.08(2H,bd), 6.86(2H,d), 7.07(2H,d), 7.23(2H,m), 7.34(3H,m)

2-(Carbomethoxy)-3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoicacid (2-8).

2-7(0.301 g) was dissolved in MeOH (30 ml), 100 mg 10% Pd-C was addedand this suspension was hydrogenated at atmospheric pressure for 5hours. The solvent was removed to give 2-8 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ1.08 (2H,m), 1.22-1.40(4H,m), 1.44(9H,S),1.63(2H, bd), 1.74(2H,m), 2.65(2N,bt), 3.20(2H,d), 3.58(1H,t,3.62(3H,S), 3.92(2H,t), 4.05(2H,m), 6.80(2H,d), 7.11(2H,d).

2-(Carbomethoxy)-3-[4-(4-piperidin-4-yl)butyloxyphenyl]propanoic acid(2-9).

2-8 (0.25 g) was dissolved in EtOAc and treated with HCl gas asdescribed for 1-9 to give pure 2-9 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ1.30-1.46(5H,m), 1.48-1.68(2H,m), 1.74(2H,m),1.95(2H,bd), 2.95(2H,t), 3.08(2H,t), 3.34(3H,m), 3.62(3H,S), 3.91(2H,t),6.80(2H,d), 7.11(2H,d).

EXAMPLE 22 ##STR44## Methyl2-Hydroxy-3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoate(2-11)

A solution of 2-2 (0.42 g, 1.0 mmoles) in THF (5 ml) was added to asolution of potassium hexamethyldisilazide (2.0 mmoles) in THF (20 ml)at -70° and this was stirred for 1.0 hour. Then, a solution ofoxaziridine 2-10 (0.52 g, 2.0 mmols)* in THF (3 ml) was added at -70°and this was stirred for 4 hours. The reaction was quenched with 10%KHSO₄ solution and this was diluted with Et₂ O (125 ml). The ether phasewas separated, washed with 10% KHSO₄ solution, H₂ O, brine and dried(Na₂ SO₄). Solvent removal gave a residue that was purified by flashchromatography on silica gel eluting with hexane/EtOAc (7:3), to givepure 2-11.

¹ H NMR (300 MHz, CDCl₃) δ1.09(2H,m), 1.22-1.41 (4H,m), 1.45(9H,S),1.65(2H,bd), 1.76(2H,m), 2.67(2H,dt), 2.90(1H,m), 3.05(1H,m),3.77(3H,S), 3.91(2H,t), 4.08(2H,bd), 4.42(1H,m), 6.81(2H,d), 7.10(2H,d).

2-Hydroxy-3-[4-(4-piperidin-4-yl)butyloxyphenyl]propanoic acid (2-12).

2-11 (0.31 g, 0.7 mmoles) was hydrolyzed with LiOH.H₂ O (0.09 g, 2.14mmoles) as described for 1-8 to give the desired acid, R_(f) 0.25(silica gel, CHCl₃ /MeOH/HOAc/95:5:1).

¹ H NMR(300 MHz, CD₃ OD) δ1.07(2H,m), 1.23-1.39(4H,m), 1.45(9H,S),1.71(4H,m), 2.72(1H,bt), 2.85(1H,m), 3.09(1H,m), 3.91(1H,t),4.05(1H,bd), 4.25(1H,m), 6.80(2H,d), 7.18(2H,d).

In addition, compounds of the instant invention which contain two R²group carbon-carbon bonds may generally be synthesized according toScheme 3. ##STR45##

The enolate of 2-2 is alkylated with methyl iodide to provide 3-1 whichis isolated. This is then methylated again to give 3-2. Deprotection ofthe carboxylate and the amine provides the final product 3-3. ##STR46##

Similarly, intermediate 2-5 is converted to its enolate and thenalkylated with methyl iodide or some other suitable agent to give 3-4.Deprotection with base and then acid provides the final product 3-5.

The amino acids used in the instant invention can include but is notlimited to the D or L form of the amino acids Alanine, Arginine,Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Glycine,Histidine, Isoleucine, Leucine, Lysine, Methionine, Orthithine,Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine andvaline. The D or L form of hydroxylysine, 3-hydroxy-proline,4-hydroxyproline, allo-isoleucine, allo-hydroxylysine, norvaline,norleucine, β-methyl proline, β-β-demethylproline, α-hydroxyproline,anhydroproline, thioproline, β-methylthioproline orβ-β-dimethylthioproline. These amino acids may be connected by amidelinkages to form polypeptides of two (2) to four (4) amino acids.

Sample alternative protecting groups that can be used in the preparationof the present invention include benzyl ester, cyclohexyl ester,4-nitrobenzyl ester, t-butyl ester, 4-pyridylmethyl ester,benzyloxycarbonyl, isonicotinyloxycarbonyl, p-methoxybenzyloxycarbonyl,t-butoxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl,adamantyloxycarbonyl, 2-(4-biphenyl)-2-propyloxycarbonyl and9-fluorenylmethoxycarbonyl.

EXAMPLE 23

In Vitro Activity

The test procedures employed to measure the anti-platelet aggregatingactivity of the compounds of the present invention are described below.

Blood was drawn into 0.1 volumes of acid citrate-dextrose (85 mM sodiumcitrate, 64 mM citric acid, 110 mM dextrose) by venipuncture from normalhuman volunteers. Platelet-rich plasma was prepared by centrifugation at400× g for 12 minutes. PGEl (5 mg/ml) was added and platelets werecollected by centrifugation at 800× g for 12 minutes. The plateletpellet was resuspended into human platelet buffer (140 mM NaCl, 7.9 mMKCl, 3.3 mM Na₂ HPO₄, 6 mM HEPES, 2% bovine serum albumin, 0.1%dextrose, pH 7.2) and filtered over Sepharose 2B that was previouslyequilibrated in human platelet buffer. Human fibrinogen (10-100 mg/ml)and Ca Cl₂ (1 mM) were added and aggregation was initiated by theaddition of 10 mM ADP. Aggregation was monitored by the initial rate ofincrease of light transmittance.

The IC₅₀ (uM) of a number of compounds claimed in the instant inventionare described below in Table 1. This table demonstrates the relativeinhibitory effects depending upon the various R² substituents on thecompound of the general formula:

                  TABLE 1                                                         ______________________________________                                         ##STR47##                                                                    R.sup.2         IC.sub.50 (uM)                                                ______________________________________                                        CH.sub.2 SO.sub.2 CH.sub.2 Ph                                                                 1.6                                                           CH.sub.2 NHC(O)Ph                                                                             3.1                                                           CH.sub.2 Ph     115.0                                                         CH.sub.2 NHSO.sub.2 C.sub.4 H.sub.9                                                           2.9                                                           CO.sub.2 CH.sub.3                                                                             5.8                                                           OH              8.6                                                           CO.sub.2 H      3.2                                                           CH.sub.2 NHCH.sub.2 Ph                                                                        18.0                                                          CH.sub.2 SO.sub.2 C.sub.4 H.sub.9                                                             0.65                                                          ______________________________________                                    

Therapeutic Treatment

Compounds of the invention may be used for inhibiting integrinprotein-complex function relating to cell attachment activity. They maybe administered to patients where inhibition of human or mammalianplatelet aggregation or adhesion is desired.

Compounds of the invention are eliminated from circulation rapidly andare particularly useful in inhibiting platelet aggregation in situationswhere a strong antithrombotic of short duration or effectiveness isneeded. Thus, they may find utility in surgery on peripheral arteries(arterial grafts, carotid endaterectomy) and in cardiovascular surgerywhere manipulation of arteries and organs, and/or the interation ofplatelets with artificial surfaces, leads to platelet aggregation andconsumption. The aggregated platelets may form thrombi andthromboemboli. Compounds of the invention may be administered to thesesurgical patients to prevent the formation of thrombi and thromboemboli.

Extracorporeal circulation is routinely used for cardiovascular surgeryin order to oxygenate blood. Platelets adhere to surfaces of theextracorporael circuit. Adhesion is dependent on the interaction betweenGPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to thesurface of the circuit. (Lluszko et al., Amer. J. Physiol., 252:H,615-621 (1987). Platelets released from artificial surfaces showimpaired hemostatic function. Compounds of the invention may beadministered to prevent adhesion.

Other applications of these compounds include prevention of plateletthrombosis, thromboembolism and reocclusion during and afterthromboembolytic therapy and prevention of platelet thrombosis,thromboembolism and reocclusion after angioplasty of coronary and otherarteries and after coronary artery bypass procedures. Compounds of theinvention may also be used to prevent myocardial infarction.

These compounds may be administered by any convenient means which willresult in its delivery into the blood stream in substantial amountincluding continuous intravenous or bolus injection or oral methods.Compositions of the invention include compounds of the invention andpharmaceutically acceptable carriers, e.g. saline, at a pH level of forexample 7.4, suitable for achieving inhibition of platelet aggregation.They may also be used in combination with anticoagulants such as heparinor warfarin. Intravenous administration is presently comtemplated as thepreferred administration route. They are soluble in water.

In one exemplary application, a suitable amount of compound isintravenously administered to a heart attack victim undergoingangioplasty. Administration occurs during or several minutes prior toangioplasty, and is in an amount sufficient to inhibit plateletaggregation, e.g. an amount which achieves a steady state plasmaconcentration of between about 0.01-30 uM, preferably between about0.03-3 uM. When this amount is achieved, an infusion of between about0.1-100 mg per kilo per min., preferably between about 1-20 mg per kiloper min. is maintained to inhibit platelet aggregation. Should thepatient need to undergo bypass surgery, administration may be stoppedimmediately and will not cause complications during surgery that wouldbe caused by other materials such as aspirin or monoclonal antibodies,the effects of which last hours after cessation of administration.

The present invention also includes a pharmaceutical compositioncomprising compounds of the present invention and tissue typeplasminogen activitor or streptokinase. The invention also includes amethod for promoting thrombolysis and preventing reocclusion in apatient which comprises administering to the patient an effective amountof compositions of the invention.

The present invention may be embodied in other specific forms withoutdeparting from the spirt or essential attributes thereof. Thus, thespecific examples described above should not be interpreted as limitingthe scope of the present invention.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modification and substitutions can bemade therein without departing from the spirt and the scope of theinvention. For example, effective dosages other than the preferred dosesas set fourth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treating forseverity of clotting disorders or emboli, or for other indications forthe compounds of the invention indicated above. Likewise, the specificpharmacological responses observed may vary according to and dependingupon the particular active compound selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be limited only by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

The following compounds are further illustrative of the scope of thepresent invention:

                                      TABLE 2                                     __________________________________________________________________________     ##STR48##                                                                    R.sup.1 Z         Y            X       R.sup.2              R.sup.3           __________________________________________________________________________             ##STR49##                                                                              (CH.sub.2).sub.3                                                                           NHCO                                                                                   ##STR50##           H                 OCH.sub.2 CO.sub.2 H                                                                  H.sub.2 N                                                                                ##STR51##   O       OCH.sub.2 Ph         CH.sub.3          CH.sub.2 CH.sub.3                                                                      ##STR52##                                                                               ##STR53##   CH.sub.2                                                                              CH.sub.2 SO.sub.2 Ph C.sub.2                                                                       H.sub.5           OCH.sub.2 CH.sub.3                                                                     ##STR54##                                                                              (CH.sub.2).sub.2 O(CH.sub.2)                                                               CO      F                    H                 Cl                                                                                     ##STR55##                                                                              (CH.sub.2).sub.6                                                                           CONH                                                                                   ##STR56##           H                 CH.sub.3 NHCH.sub.2                                                                    ##STR57##                                                                               ##STR58##   NHSO.sub.2                                                                             ##STR59##           CH.sub.3          CH.sub.3 SO.sub.2 CH.sub.2                                                             ##STR60##                                                                               ##STR61##   CHCH.sub.2                                                                            CH.sub.2 NHSO.sub.2 CH.sub.2                                                  CH.sub.3             C.sub.2                                                                       H.sub.5           CH.sub.2 CO.sub.2 H                                                                    ##STR62##                                                                               ##STR63##   CH.sub.2                                                                               ##STR64##           H                 F                                                                                      ##STR65##                                                                              (CH.sub.2).sub.5                                                                           O       CH.sub.2 OCH.sub.3   H                 __________________________________________________________________________

What is claimed is:
 1. A compound of the formula: ##STR66## and thepharmaceutically acceptable salts thereof, wherein R¹ is chosen fromH,C₁₋₆ alkyl, phenylC₁₋₁₀ alkyl, phenyl, carboxy, C₁₋₆ alkyloxy,carboxyC₀₋₆ alkyl, carboxyC₀₋₆ alkyloxy, hydroxyC₀₋₆ alkyl, C₁₋₄alkylsulfonylC₀₋₆ alkyl, C₀₋₄ alkylaminoC₀₋₆ alkyl, C₀₋₁₀phenylalkylaminoC₀₋₆ alkyl, C₂₋₁₀ acylaminoC₀₋₆ alkyl, C₁₋₄carboalkoxyC₀₋₆ alkyl, or halogen; R² is independentlyH, halogen,hydroxy, C₁₋₆ alkyloxy, phenylC₀₋₄ alkyl, phenylC₀₋₆ alkyloxy, C₁₋₆alkyl, wherein the alkyl group is unsubstituted or substituted with oneor more groups chosen from: hydroxy, C₁₋₄ alkyloxy, aminoC₁₋₁₀alkylcarbonyl, phenyl C₀₋₁₀ alkylcarbonyl, C₁₋₆ alkylcarbonyl amino,phenylC₀₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio,phenylC₀₋₁₀ alkylsulfonyl, phenylC₁₋₆ alkylthio, C₁₋₆alkylsulfonylamino, phenylC₀₋₁₀ alkylsulfonylamino, C₁₋₁₀ alkyloxycarbonylamino, phenylC₀₋₆ alkylamino, phenylC₀₋₆ alkyl carbonylamino,amino, carboxyl, phenyl,; carboxyl, C₁₋₆ alkylcarbonyl, phenylC₀₋₁₀alkylcarbonyl, C₁₋₆ alkyloxycarbonylaminoC₁₋₆ alkyl, C₀₋₆alkylaminocarbonylaminoC₁₋₆ alkyl, C₁₋₆ alkyloxycarbonyl, or phenylC₀₋₆alkyloxycarbonylamino C₁₋₆ alkyl; R³ isH, C₁₋₆ alkyl, or phenylC₁₋₁₀alkyl; Z is a 6-membered monocyclic saturated ring system containing onenitrogen as the single heteroatom and either unsubstituted orsubstituted with R⁴ or R⁵ wherein R⁴ and R⁵ are independently H, C₁₋₆alkyl, or phenyl C₁₋₁₀ alkyl wherein said alkyl groups are unsubstitutedor substituted with C₁₋₄ alkyloxy, carboxy C₀₋₆ alkyl, hydroxy, orhalogen; Y is-C₁₋₁₀ alkyl- either unsubstituted or substituted with oneor more groups selected from R⁴ or R⁵ ; -C₄₋₈ cycloalkyl-, -phenyl-,-C₀₋₃ alkyl phenylC₀₋₃ alkyl-, -C₀₋₃ alkyl phenylC₀₋₃ alkylcarbonyl-,-C₀₋₃ alkyl phenylC₀₋₃ alkylcarboxamido-, -C₀₋₃ alkyl phenyloxyC₀₋₃alkyl-, -C₀₋₃ alkyloxyC₀₋₆ alkyl-, ##STR67## X is --O--, --S--, --SO--,--SO₂ --, --CO--, --NR⁴ CO--, --CONR⁴ --, --CH₂ --, --CH═CH--, --C═C--,--NR⁴ CS--, --CSNR⁴ --, --SO₂ NR⁴ --, or --NR⁴ SO₂ --.
 2. A compoundaccording to claim 1 wherein said compound is:Methyl3-[4-(4-N-t-Butyloxycarbonylpiperdin-4-yl)-butyloxyphenyl]-2(benzyl)propanoate;or 3-[4-(4-Piperidin-4-yl)butyloxyphenyl]-2-(benzyl)-propanoic acid; orMethyl2-carbomethoxy-3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoate;or 2-Carboxy-3-[4-(4-Piperidin-4-yl)butyloxyphenyl]-propanoic acid; orMethyl2-(Benzyloxycarbonyl)-3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoate;or2-(Carbomethoxy)-3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoicacid; or2-(Carbomethoxy)-3-[4-(4-piperidin-4-yl)butyloxyphenyl]propanoic acid;or Methyl3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)-butyloxyphenyl]propanoate;or Methyl2-Hydroxy-3-[4-(4-N-t-butyloxycarbonylpiperidin-4-yl)butyloxyphenyl]propanoate;or 2-Hydroxy-3-[4-(4-piperidin-4-yl)butyloxyphenyl]-propanoic acid.
 3. Acompound according to claim 1 wherein said compound is:Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)-butyloxy]phenylmethyl-3-(n-butylthio)propanoate;or Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)-butyloxy]phenylmethyl-3-(n-butylsulfonyl)propanoate;or2-[4-(4-Piperidin-4-yl)butyloxy]phenylmethyl-3-(n-butylsulfonyl)propanoicacid; or Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)-butyloxy]phenylmethyl-3-(benzylthio)propanoate;or Methyl2-[4-(4-piperidin-4-yl)-butyloxy]phenylmethyl-3-(benzylsulfonyl)propanoate;or2-[4-(Piperidin-4-yl)butyloxy]phenylmethyl-3-(benzylsulfonyl)propanoicacid; or Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)-butyloxy]phenylmethyl-3-(benzylamino)propanoate;or 2-[4-(Piperidin-4-yl)butyloxy]phenylmethyl-3-(benzylamino)propanoicacid; or Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)-butyloxy]phenylmethyl-3-(amino)propanoate;or Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)-butyloxy]phenylmethyl-3-(benzoylamino)propanoate;or 2-[4-(Piperidin-4-yl)butyloxy]phenylmethyl-3-(benzoylamino)propanoicacid; or Methyl2-[4-(4-N-t-Butyloxycarbonylpiperidin-4-yl)-butyloxy]phenylmethyl-3-(n-butylsulfonylamino)propanoicacid, or2-[4-(Piperidin-4-yl)butyloxy]phenylmethyl-3-(n-butylsulfonylamino)propanoicacid.
 4. A method of blocking fibrinogen from acting at its receptorsite in a mammal, including a human comprising administering apharmacologically effective amount of a compound as claimed in claim 1.5. A method of preventing thrombus and embolus formation in a mammal,including a human, in need thereof, comprising administering apharmacologically effective amount of a compound as claimed in claim 1.6. A method of treating thrombus and embolus formation in a mammal,including a human, in need thereof, comprising administering apharmacologically effective amount of a compound as claimed in claim 1.7. A method of inhibiting aggregation of blood platelets in a mammal,including a human, comprising administering a pharmacologicallyeffective amount of a compound as claimed in claim
 1. 8. Apharmaceutical composiiton, comprising a compound as claimed in claim 1,and a pharmaceutically acceptable carrier.
 9. The composition as claimedin claim 8, in which said pharmaceutically acceptable carrier consistsof a sustained release pharmaceutical formulation.
 10. A pharmaceuticalcomposition for inhibiting the binding of fibrinogen to blood plateletsin a mammal, including a human, comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 11. A pharmaceutical compositionfor inhibiting the aggregation of blood platelets in a mammal, includinga human, comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 12. A composition for preventing thrombus or embolusformation in a mammal, including a human, pharmaceutically acceptablecarrier.
 13. A composition for treating thrombus or embolus formation ina mammal, including a human, comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 14. A method for inhibiting theaggregation of blood platelets in a mammal, including a human,comprising administering the composition of claim
 8. 15. A method forpreventing or treating thrombus or embolus formation in a mammal,comprising administering the composition of claim 9.